Re: An epigenetic model of loss and vestigialization of limbs in

On Mar 10, 3:20 am, "Perplexed in Peoria" <jimmene...@xxxxxxxxxxxxx>
wrote:
<CNCa...@xxxxxxx> wrote:

On Mar 9, 6:27 pm, "Perplexed in Peoria" <jimmene...@xxxxxxxxxxxxx>
wrote:

<CNCa...@xxxxxxx> wrote:
On Mar 9, 12:11 am, "Perplexed in Peoria" <jimmene...@xxxxxxxxxxxxx>
wrote:
<CNCa...@xxxxxxx> wrote:

On Mar 7, 10:40 am, "Perplexed in Peoria" <jimmene...@xxxxxxxxxxxxx>
wrote:
<CNCa...@xxxxxxx> wrote:
[snip]
5. The python's CNS, in response to the evolutionary loss, changes
the structure of a relevant neural circuit (the structure and
computational properties of neural circuits change in response to the
new input). The changed neural circuit, in turn, produces a change in
the epigenetic information it provides to the egg/sperm cell that
induces the same change in the CNS of the offspring.
[snip]
---------------
PiP:
As in the famous Sydney Harris cartoon, I think you need more
detail regarding that last step. The changed neural circuit produces
a change in the epigenetic information in the gamete - no problem.
But that it produces exactly the right epigenetic info change so as to
induce the same CNS structure change in the offspring? That strikes
me as an incredible coincidence unless you have some principle
(like Watson-Crick base-pairing in genetics) which guarantees that
information is preserved through reproduction.

So what is that proposed principle?

Cabej:
I certainly agree that I need more detail regarding the last
step of my model. Just like you, I would like to have information
on how the change in the gametic epigenetic information is
reflected in the structure of a specific neural circuit in a way
that makes it capable of producing and depositing in the gamete
the same epigenetic factor.

This is what we don't know.
-----------
PiP:
Whereas, in the genetic model, this is a non-problem. We know
exactly how genetic inheritance works. The only thing we don't
know in detail is how the genes determine the structure of the
CNS during development. But your model has the same problem.
You don't know how the epigenetic factors in the zygote determine
the CNS either.

Cabej:
First of all where is the genetic model?  I have urged John
and anyone here to present a model that would account for
several issues, with each of them being crucial to its validation.

1.The determination of spatial patterns of expression of  genes in
limbs (experimentally demonstrated binary neural control of receptor
expression does this routinely)

2.The temporal patterns of expression (the genome has no developmental
clock and the CNS (hypothalamic) clock controls and resets all the
cell clocks throughout the animal body).

3.The directed migration of neural crest cells to their target sites
site, including limb development.

4. The nature and origin of information the neural crest cells are
provided by the neural tube/brain before leaving the neural tube,
which they use to instruct limb bud cells on what type of cell
they have to differentiate into.
“The proper program of events governing the migration of crest may
need first to be established in the hindbrain to allow migratory cells
to interpret and respond to environmental signals (Trainor, P.A. et
al. 2002. Development 129: 433-442).
“Neural crest cells  function as the dominant source of spatial and
temporal patterning information via the regulation of genes” (Eames,
B.F. and Schneider, R.A, 2005. Development 132: 1499-1509) essential.

5. Most of the limbless species initially activate the “limb-
determining” genes, form AER and ZPA, and even develop limbs to
advanced stages before starting the programmed cell death of limb
tissues, which in both invertebrates and vertebrates is neurally
controlled. This shows that these limbless species havefunctionally
unaltered all the genes (including regulatory regions).

Before formation of the operational CNS, a programmed cell death is
activated  during early development by maternal factors and during
later life is under neuroendocrine control.
The early idea that the cause of the loss of limbs was an “arrested
development”, was shown to contradict some embryological observations
on limbless snakes, lizards, and cetaceans. In general, during the
early embryonic development some of these species develop limb buds
and form an AER (apical ectodermal ridge), which later disappear
gradually (Bejder, L. and Hall, B.K. 2002. Evolution & Development 4:
445-458).
Embryos of the limbless river mammal, Stenella attenuata also develop
limb buds. The limb bud grows to reach a length of 10-30 cm before
starting regressive processes that lead to their reduction and total
disappearance.

6. Atavisms as sudden (intragenerational) appearance of morphological
traits lost millions of years ago and involving thousand of genes. The
epigenetic model can explain it with the sudden activation of neural
circuits.
Individuals with vestigial hind limbs are observed, at a low
frequency, among the adult populations of the spotted dolphin
(Sedmera, D. et al., 1997. European Journal of Morphology35: 25-30).
The sperm whale (Physeter catadon) is the only toothed whale with a
hind limb skeleton (15 cm long), although its expression is variable
(Hall, B.K.1995. Nature Genetics 10: 126-127).

I consider your feedback a real help and I appreciate it.
However, I would like to know whether, in your opinion, John's
genetic modell can account for any of the above problems  crucially
related to its validation of the above. Which one of the six problems
could that genetic model, in your opinion, account for?
--------------
PiP:
All of them, I think.

This is a real surprise. I thought that no genetic model can account
for any of those problems. I am curious to know what your unexpected
solutions might be.

The genetic model is identical to your epigenetic
model except for the cause of the changed CNS in pythons without
forelimbs (as compared to their presumed ancestors with forelimbs).
In the genetic model, a genetic mutation in the ancestral limbless
python cause the CNS to change its signalling pattern at the relevant
locations.  That mutation was heritable, because all mutations are
heritable.  And it was fixed in the population because pythons neither
need nor use forelimbs, and the pythons that still had them died out.

First,  there is experimental evidence that no mutation has occurred
in enzymes responsible for RA synthesis and the evidence that
a "mutation in a gene has changed spatial pattern of at the relevant
locations" is ZERO. So, in plain English, you have failed in your
attempt to account for the change in the spatial pattern of
expression of RA by the spinal cord and by brachial nerves
from a genetic point of view (with the occurrence of a
hypothetical mutation).
------------------
PiP:
No, what you mean to say is that I have failed to pinpoint the
mutation and its mode of operation.  But I do account for
the heritability, which I think is the more important problem.

What I meant is exactly what I said:

"There is experimental evidence that no mutation has occurred
in enzymes responsible for RA synthesis and the evidence that
a "mutation in a gene has changed spatial pattern of at the relevant
locations" is ZERO. So, in plain English, you have failed in your
attempt to account for the change in the spatial pattern of
expression of RA by the spinal cord and by brachial nerves
from a genetic point of view (with the occurrence of a
hypothetical mutation)."
I take your response a tacit confirmation of the fact that you
can't even imagine, let alone find evidence to account for the
change in the spatial pattern of expression of RA by the
spinal cord and by brachial nerves from a genetic point of
view (with the occurrence of a hypothetical mutation). It is
a good thing you are admitting your failure to account from
a genetic view for the spatial pattern of expression.

But I do account for the heritability, which I think
is the more important problem.

Really? Read what you wrote just 3 days ago:
"The only thing we don't know in detail is how the genes
determine the structure of the CNS during development."
(PiP, March,7).What did you learn in the meantime that
makes you believe you can account for the "genetic"
heritability of the CNS?

What you can account for is the "heritability of proteins
only. I will
be happy to immediately discuss with you in a special
thread if you can account for anything besides the
heritability of proteins. For now, II don't want to be
distracted from 6 issues. "Stay the course" and
prove that you can account for these issues from your,
in your expression, "genecentrist" view.

You have accounted for neither the mechanism nor the heredity.

The same distracting tactics.

However, you do have a point that it is unfair to expect that
account from you, since the genetic model has been investigated
for decades by well-funded and well-educated researchers,
while you are a lone kook.
----------------
I like your rhetoric but I feel sorry to see you so hopeless as to
resort to the fallacious argumentum ad populum, as a proof of
anything.

Now you have to deal with the other five  issues that I believe
no genetic model can account for.  Since the "model" you
intend to defend is in fact a hypothesis, you can't use other
hypotheses, and less so statements, to prove it.
Evidence only is acceptable.
------------
PiP:
My evidence is the same as yours.  Why can't you see this?
------------
You have presented no relevant evidence at all. If I am exaggerating
you can prove I am wrong.

For your convenience, below I am presenting these issues
in the form I phrased first in this thread.

2.The temporal patterns of expression (the genome has no developmental
clock and the CNS (hypothalamic) clock controls and resets all the
cell clocks throughout the animal body).
----------------
PiP: No one here disputes this.  Epigenetics plays a role in the development
of the individual - providing both the 'clock' and the 'GPS' system.  

Good thing you are admitting that for it implies that genes do not
know when to switch on/off. Let me present just one example.
Thousands of genes are centrally regulated to work or not, according
to the circadian clock, which
is represented by neurons of the hypothalamic SCN (suprachiasmatic
nucleus), the so-called SCN circadian pacemaker. The pacemaker has
its own subjective 24 hours rhythm but also uses environmental photic
stimuli to adapt the expression of genes throughout the animal body to
seasonal day-night changes.
The SCN pacemaker receives continuous input from peripheral clocks
which are coupled with the peripheral cell metabolism. It detects
deviations and via neural and neurohormonal signals continulually
resets the rhythm in peripheral clocks.
The circadian system, regulated and coordinated by the hypothalamic
circadian pacemaker, in mammals performs the temporal control of
virtually every biochemical, physiological, and neurobiological
process (Fuller, P.M. 2006. Journal of Biological Rhythms 21:
177-184). It is estimated that expression of 8-10% of genes (about
2,000 thousand genes are switched on/off according to hypothalamic
signals (Storch, K.F. et al. 2002. Nature 417: 78-83).
Hence, the evolutionary changes in the circadian expression of these
genes in various animal species require a change in the structure and
(related) computational properties of the CNS. and there is evidence
that these circuits can change without changes in genes.

However, the genome provides the "map database".  
-----------------
I cannot understand anything at all what you mean by that.
But I am sure you could help me understand it if you illustrate
your idea with an example. Can you?

And genetics is the thing that changes in the course of evolution.

Oh, you admitted earlier that epigenetics also evolved
(remember cytoplasmic factors, individual development,
animal behavior the brain and its computational and cognitive
properties. The problem is which is the cause and which
is the effect. No serious neurobiologists would tell you that the
behavior, cognitive capabilities and neuronal connections of
human brain differ from those of a chimp because of changes in
genes.

There are always news about the discovery of genes for
homosexualism, genes for geniuses etc. but these are
just remnants of the century old "one-gene-one character" era.

3.The directed migration of neural crest cells to their target sites
site, including limb development.
-----------------
PiP: Again, this is development - not heredity or evolution.
-----------------
Everything, including you and me, come from development,
and our characters have no other way to arise but via
development. The development has a genetic and epigenetic
basis. The information these cells use to find their target sites
and the information they use to transform themselves and the local
cells in the right types of cells in target sites is not genetic.

Please don't tell me about any cell-cell interactions ;
that's not what researchers have concluded:

"Neural crest cells function as the dominant source of spatial
and temporal patterning information via regulation of genes
essential to cranial feather morphogenesis" (Eames, B.F. and
Schneider, R.A. 2005. Development 132: 1499-1509).

"Neural crest cells provide patterning information for
beak morphology. Not only do neural crest cells direct
their own morphogenesis, they also pattern non-neural
crest beak tissues in a manner characteristic of the donor
species." (Schneider, R.A. and Helms, J.A. 2003. Science
299: 565-568).

Commenting on their experimental evidence from neural
crest transplantions, Tucker and Lumsden write about

"the existence of a species-specific prepattern in the neural
crest cells" (Tucker, A.S. and Lumsden, A. 2004. Evolution &
Development 6: 32-40)) which is

"Morphogenetically prespecified in respect of its branchial
skeletal derivatives, that is, that information for the number,
size, shape and position of its individual elements is already
determined in these cells when they are still in the neural folds.
This positional information would somehow be preserved
after they delaminate from the neural tube and migrate into
the branchial arches before being read out as spatial pattern
of chondrogenesis and osteogenesis." (Tucker, A.S. and
Lumsden, A. 2004. Evolution & Development 6: 32-40)

"The proper program of events governing the migration of
crest may need first to be estabklished in the hindbrain."
(Trainor, P.A. et al. 2002. Development 129: 433-442)

So, experimenters tell us that neural crest cells are provided
with epigenetic, NOT GENETIC, information on where to go
and what to do before they delaminate from the neural tube
and this epigenetic information determines the spatial and
temporal patterning of developing structures in the target sites.

So, the morphogenetic role of the neural crest cells in limb
development is epigenetically not genetically determined
and any evolutionary change in that role requires a change
in the epigenetic information thhe neural crest cells are
provided with before they delaminate from the CNS.

4.The nature and origin of information the neural crest cells are
provided with before leaving the neural tube, which they use to
instruct limb bud cells on what type of cell they have to
differentiate into.
“The proper program of events governing the migration of crest may
need first to be established in the hindbrain to allow migratory cells
to interpret and respond to environmental signals (Trainor, P.A. et
al. 2002. Development 129: 433-442).
“Neural crest cells  function as the dominant source of spatial and
temporal patterning information via the regulation of genes” (Eames,
B.F. and Schneider, R.A, 2005. Development 132: 1499-1509) essential.
----------------
PiP:  More development.  Epigenetics is the source of spatial and
temporal differentiation.  Obviously so, since the genetics is the same
in every cell for the lifetime of the organism.  The only mystery here
is why you don't realize that the genetic model accepts this.

By accepting this you are admitting that epigenetics NOT GENETICS,
can account for the role of neural crest in limb development.
-----------------
5. Most of the limbless species initially activate the “limb-
determining” genes, form AER and ZPA, and even develop limbs to
advanced stages before starting the programmed cell death of limb
tissues, which in both invertebrates and vertebrates is neurally
controlled. This shows that these limbless species have functionally
unaltered all the genes (including regulatory regions).
-------------
PiP:
Not ALL the genes.  Just the ones downstream of the ones that
evolved.
-------------
Do you know of any upstream "limb-determining gene" that is
altered in animals that first develop limbs and then eliminate
them? I don't know. Since you obviously don't know, why
should anyone believe that an unidentified upstream gene has
changed.
Besides, since the all the genes for the apoptosis signal cascade
are functional in other limbed species, do you know of any
gene that changed in such a way that instructed the nervous system
where to start the aptoptotic signal cascade for eliminating limbs?

Before formation of the operational CNS, a programmed cell death is
activated  during early development by maternal factors and during
later life is under neuroendocrine control.
The early idea that the cause of the loss of limbs was an “arrested
development”, was shown to contradict some embryological observations
on limbless snakes, lizards, and cetaceans. In general, during the
early embryonic development some of these species develop limb buds
and form an AER (apical ectodermal ridge), which later disappear
gradually (Bejder, L. and Hall, B.K. 2002. Evolution & Development 4:
445-458).
Embryos of the limbless river mammal, Stenella attenuata also develop
limb buds. The limb bud grows to reach a length of 10-30 cm before
starting regressive processes that lead to their reduction and total
disappearance.
----------------
PiP:  And what is there in this that you think argues against the genetic
model?  

You have accepted the burden of explaining from a genecentric
point of view the loss of limbs. Now do it. Account for the
elimination of limbs in animals that have all the genes to build
limbs and build limbs. Explain from a genetic (mutation) view and
show how a change in some gene might instruct activation of
the apoptotic signal cascade there where it is needed not
somewhere else in the body.

As I said, the only difference between my model and yours
regards the reasons why the CNS is different in pythons with and without
forelimbs.
---------------
And your model posits that the genome sends instructions
to the CNS. But can you tell which cell's genome sends instructions
to what part of the CNS and how and in what form that
message is sent to the CNS?

6. Atavisms as sudden (intragenerational) appearance of morphological
traits lost millions of years ago and involving thousand of genes. The
epigenetic model can explain it with the sudden activation of neural
circuits.
Individuals with vestigial hind limbs are observed, at a low
frequency, among the adult populations of the spotted dolphin
(Sedmera, D. et al., 1997. European Journal of Morphology35: 25-30).
The sperm whale (Physeter catadon) is the only toothed whale with a
hind limb skeleton (15 cm long), although its expression is variable
(Hall, B.K.1995. Nature Genetics 10: 126-127).

Atavistic skeletal elements can be surprisingly complete; 79 cm long
bones in 125 cm long left and right “hindlimbs” in a female humpback
whale. (Bejder, L. and Hall, B.K. 2002. Evolution & Development 4:
445-458 )
Tail loss, to various extents (from two thirds of its length to total
loss), is observed in 58% of individuals (of the same genotype) of a
large population of tiger snakes in Western Australia (Aubret, F. et
al., 2005. Journal of Experimental Zoology Part A. Comparative
Experimental Biology 303: 894-903).
-----------------
PiP:  So, as I understand you, you are claiming that the loss of forelimbs
was due to a simple epigenetic change (mutation) and that you get an
atavism when that original epigenetic change is reversed.
But it strikes you as completely incredible that the loss of forelimbs
could be due to a simple genetic change (mutation) because you do
not understand how you could get an atavism when the original
genetic change is reversed.

This defies common sense.

First, nondeleterious mutations that affect 58 (or 37%)
percent of individuals and occurring generation after
generation? This defies common sense. Even elementary
genetics tells us that this is impossible to occur.

Secondly, from a theoretical neoDarwinian standpoint, the
irreversibility of evolution has been a tenet of neoDarwinism
for the simple reason that during the long periods of time
(many millions of years) since these animals lost their organs,
in the absence of the action of natural selection,
a great number of mutations will be accumulated in some
(strictly organ-specific) genes that will make them
nonfunctional and make reversion of long-lost organs
impossible. I can't believe you deny Dollo's law?
You have recent neoDarwinian publications defending
that law, the genetic law of irreversibility of evolution
(Evolution 62 (11):2727-2741. 2008).

I am sorry to tell you, but you obviously failed to account
for any of the six issues that any genetic hypothesis of
the evolutionary loss of limbs has to. I don't believe anyone
else could have done better.


At this time, I have to leave. I hope to be back in a month's time.

[snip remainder]

Regards,

N.C.

.

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